Estrogen mimics at low doses change how brain cells manage dopamine.

Mar 03, 2009

Alyea, RA and CS Watson. 2009. Xenoestrogens alter dopamine transport and trafficking. Environmental Health Perspectives doi:10.1289/ehp.0800026.

For the first time, scientists find that extremely low levels of some types of environmental estrogens disrupt specialized brain cells and their ability to regulate brain chemistry. All of the EEs tested changed the way cells released and reabsorbed dopamine, an important chemical messenger that governs movement and pleasure.
J.P. Myers
In some cases, the responses were stronger when natural estrogens were mixed with one EE, as exposures most likely occur in people and animals. These changes may explain how EEs contribute to nervous system diseases, such as Parkinsons and schizophrenia, that are caused by abnormal dopamine responses.
Xenoestrogens and other estrogen mimics are environmental contaminants that act in ways similar to -- but not exactly like -- natural hormones such as estrogen. Exposure to these chemicals, particularly at very low levels, can cause biological outcomes that are not predicted by traditional experimental procedures.


Xenoestrogens, environmental estrogens, or simply, estrogen mimics are natural and synthetic compounds found almost everywhere in the environment. They can contaminate humans, animals, plants, soil, water and air.

The widely variable substances are present in plastics, PCBs, pesticides and herbicides, pharmaceutical products, and personal care products. While the amounts found in these products are often extremely small, the sheer volume of items containing them makes exposure unavoidable.

People around the planet are exposed to estrogenic compounds on a daily basis. The constant exposure to low levels may contribute to the potential to harm human health.

Mounting evidence suggests that exposure to low levels of some EEs -- especially during development -- can cause a number of effects that can lead to disease and reproductive problems later in life. Effects seen at lower doses may not occur at higher doses or those at middle doses may not appear at the low or high exposures tested. These variations -- common with hormones and environmental disrupting compounds -- are known as nonmonotonic dose responses

Prior laboratory studies show estrogen mimics can affect the brain by altering important signaling chemicals that are regulated by estrogen hormones.

Dopamine is one of these specialized brain chemicals. Dopamine helps brain and nerve cells communicate with one another. Its actions affect heart/circulation (blood pressure), hormones (reward/pleasure) and nerve function (movement). Dopamine is considered a neurotransmitter -- a messenger that carries signals from one nerve cell to another -- and a hormone -- a molecule that sends control messages to the hormonal system. 

A number of diseases -- including Parkinsons, schizophrenia, attention deficit disorder and addiction -- are attributed to problems with dopamine levels in the brain.

What did they do?

The authors tested whether different types of environmental estrogens (EEs) affect dopamine signaling in rat brain cells. They tested the compounds by themselves and then combined with estrogen hormones, as would occur in people and animals. Levels tested were low, similar to what might be present in the brains of people in the general population.

Cells derived from rat brains, called PC12 cells, were exposed to six estrogen mimics, five of which are commonly found in the environment. The compounds represented three major types of EEs: pharmaceuticals (diethylstilbestrol or DES), plastic additives (BPA, nonylphenol) and pesticides (DDE, dieldrin and endosulfan).

After exposing the cells, changes in dopamine regulation were measured. Normally, brain cells release dopamine in response to an electrical or chemical stimulus. After a period of time, cells reabsorb the dopamine and store it for the next stimulus and release. The researchers measured both processes to determine if the estrogen mimics affected release, uptake or both.

First, the authors measured how dopamine regulation changed through time. A single, environmentally relevant dose (1nM or 1 part per billion) of the estrogen mimics was added to cells. The amount of free dopamine outside of the cells was measured every minute for up to 20 minutes.

Second, they chose the time point at which dopamine release was maximum for each of the estrogen mimics and used that time point to ask if the maximum dopamine release changed using a range of doses for each chemical.

Finally, in arguably the most important experiment of the paper, the authors tested two estrogen mimics in combination with the natural estrogen hormone 17-beta-estradiol. This experiment replicates what would most likely happen in people exposed to the chemicals.

Chemicals and normal hormones occur together in organisms. It is the combination of the two (or more) that may have the most profound (and realistic) impact on the chemical signals and ultimately, health.

What did they find?

In the first experiment, when compared to controls, treatment with 1 ppb DES, DDE and dieldrin all caused a relatively slow but steady release of dopamine, followed by either a leveling off or a reabsorption of dopamine. Nonylphenol caused a slight release of dopamine, followed by a rapid and dramatic reabsorption of the dopamine. Interestingly, bisphenol A caused a biphasic response with two separate cycles of dopamine release and reabsorption.

In the second experiment, the authors measured changes in dopamine regulation at a single time point across a range of concentrations. All of the estrogenic mimics had more activity in the middle concentrations rather than at either the lower or higher levels (displaying a non-monotonic dose response curve). Non-monotonic dose response curves generally follow an inverted U shape, and are commonly seen at extremely low concentrations of hormones or hormone mimics.

Finally, the authors tested how a dual exposure to either DDE or bisphenol A and 17-beta-estradiol would affect dopamine regulation. The insecticide DDE added with the estrogen increased dopamine release across a range of doses.

Combining estrogen and bisphenol-A affected dopamine regulation in a way not predicted by the individual responses to either estrogen or bisphenol A. Specifically, while bisphenol A caused a rapid reabsorption of dopamine at the lowest dose tested, bisphenol A and estrogen together mediated dopamine release. Moreover, at an intermediate dose where neither estrogen nor bisphenol A affected dopamine release, the combination of the two caused significant dopamine release.

Each of the five estrogenic chemicals tested affected in different ways how rat brain cells release and reabsorb dopamine. All acted at very low levels -- in the parts per billion to parts per trillion range (less than a teaspoon mixed into an Olympic sized swimming pool).

The responses were not linear across the doses tested; that is they did not increase steadily as doses increased. The most profound effects were observed in the middle dose ranges of the EEs tested. The higher levels did not affect dopamine in the same way. Dose response experiments that show an inverted U response are referred to as non-monotonic and are very common with xenoestrogen responses.

The EEs acted through hormone receptors on the surface of the cell membrane, instead of through receptors inside the nucleus. Surface receptors are much more sensitive to low levels of exposure and their effects can take place much more rapidly than receptors inside the nucleus.  During the past 5 years, the surface receptors have received considerable attention because of their unique traits that better explain how some of the effects seen when testing EEs occur.

Finally, when two of the xenoestrogens were tested in combination with estrogen, the effects on dopamine regulation were different than when each of the chemicals was tested individually. The results of these experiments are most likely what is happening in the real world where humans are exposed to mixtures of contaminants. Moreover, these contaminants are interacting with and interfering with normal biological regulatory factors, including, but not limited to, hormones.

If the observations found in this study using brain cells also occur in the brains of animals and people, the implications are alarming. Specifically, chemicals common in the products, air, water and food are potentially capable of profoundly altering brain chemistry at extremely low levels; levels that most humans and many animals are exposed to on a daily basis.



Myers, J.P. and W. Hessler. 2007. Does the dose make the poison? Environmental Health News.

 Parkinson's Disease. National Parkinson Foundation.

 Understanding Addiction: Dopamine. Addiction Science Research and Education Center, University of Texas at Austin.



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